研究活動情報

• 2023年08月 日本筋学会, Young Investigator Award 優秀賞


• 2019年08月 日本筋学会, Young Investigators Award 最優秀賞, 骨格筋組織幹細胞におけるRor1およびRor2の機能解析


• 2014年01月 コエンザイムQ協会, 奨励賞, CoQ10によるプロテインキナーゼCの 機能制御を介した創傷治癒促進効果

• ALDH7A1 protects against ferroptosis by generating membrane NADH and regulating FSP1.

  Jia-Shu Yang, Andrew J Morris, Koki Kamizaki, Jianzhong Chen, Jillian Stark, William M Oldham, Toshitaka Nakamura, Eikan Mishima, Joseph Loscalzo, Yasuhiro Minami, Marcus Conrad, Whitney S Henry, Victor W Hsu

  Ferroptosis is a form of cell death due to iron-induced lipid peroxidation. Ferroptosis suppressor protein 1 (FSP1) protects against this death by generating antioxidants, which requires nicotinamide adenine dinucleotide, reduced form (NADH) as a cofactor. We initially uncover that NADH exists at significant levels on cellular membranes and then find that this form of NADH is generated by aldehyde dehydrogenase 7A1 (ALDH7A1) to support FSP1 activity. ALDH7A1 activity also acts directly to decrease lipid peroxidation by consuming reactive aldehydes. Furthermore, ALDH7A1 promotes the membrane recruitment of FSP1, which is instigated by ferroptotic stress activating AMP-activated protein kinase (AMPK) to promote the membrane localization of ALDH7A1 that stabilizes FSP1 on membranes. These findings advance a fundamental understanding of NADH by revealing a previously unappreciated pool on cellular membranes, with the elucidation of its function providing a major understanding of how FSP1 acts and how an aldehyde dehydrogenase protects against ferroptosis.

  2025年04月, Cell, 英語, 国際誌

  研究論文（学術雑誌）


• Ror2 signaling regulated by differential Wnt proteins determines pathological fate of muscle mesenchymal progenitors

  Koki Kamizaki, Mitsuko Katsukawa, Ayano Yamamoto, So-ichiro Fukada, Akiyoshi Uezumi, Mitsuharu Endo, Yasuhiro Minami

  Abstract Skeletal muscle mesenchymal progenitors (MPs) play a critical role in supporting muscle regeneration. However, under pathological conditions, they contribute to intramuscular adipose tissue accumulation, involved in muscle diseases, including muscular dystrophy and sarcopenia, age-related muscular atrophy. How MP fate is determined in these different contexts remains unelucidated. Here, we report that Ror2, a non-canonical Wnt signaling receptor, is selectively expressed in MPs and regulates their pathological features in a differential ligand-dependent manner. We identified Wnt11 and Wnt5b as ligands of Ror2. In vitro, Wnt11 inhibited MP senescence, which is required for normal muscle regeneration, and Wnt5b promoted MP proliferation. We further found that both Wnts are abundant in degenerating muscle and synergistically stimulate Ror2, leading to unwanted MP proliferation and eventually intramuscular adipose tissue accumulation. These findings provide evidence that Ror2-mediated signaling elicited by differential Wnts plays a critical role in determining the pathological fate of MPs.

  Springer Science and Business Media LLC, 2024年10月, Cell Death & Disease, 15(10) (10)

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• Role of the Ror family receptors in Wnt5a signaling.

  Koki Kamizaki, Yasuhiro Minami, Michiru Nishita

  Ror-family receptors, Ror1 and Ror2, are type I transmembrane proteins that possess an extracellular cysteine-rich domain, which is conserved throughout the Frizzled-family receptors and is a binding site for Wnt ligands. Both Ror1 and Ror2 function primarily as receptors or co-receptors for Wnt5a to activate the β-catenin-independent, non-canonical Wnt signaling, thereby regulating cell polarity, migration, proliferation, and differentiation depending on the context. Ror1 and Ror2 are expressed highly in many tissues during embryogenesis but minimally or scarcely in adult tissues, with some exceptions. In contrast, Ror1 and Ror2 are expressed in many types of cancers, and their high expression often contributes to the progression of the disease. Therefore, Ror1 and Ror2 have been proposed as potential targets for the treatment of the malignancies. In this review, we provide an overview of the regulatory mechanisms of Ror1/Ror2 expression and discuss how Wnt5a-Ror1/Ror2 signaling is mediated and regulated by their interacting proteins.

  2024年05月, In vitro cellular & developmental biology. Animal, 60(5) (5), 489 - 501, 英語, 国際誌

  研究論文（学術雑誌）


• Role of Wnt5b-Ror1 signaling in the proliferation of pancreatic ductal adenocarcinoma cells.

  Natsuko Yamauchi, Mako Otsuka, Tomohiro Ishikawa, Yoshihiro Kakeji, Akira Kikuchi, Atsuhiro Masuda, Yuzo Kodama, Yasuhiro Minami, Koki Kamizaki

  Pancreatic ductal adenocarcinoma (PDAC) is one of the most refractory cancers with the worst prognosis. Although several molecules are known to be associated with the progression of PDAC, the molecular mechanisms underlying the progression of PDAC remain largely elusive. The Ror-family receptors, Ror1 and Ror2, which act as a receptor(s) for Wnt-family ligands, particularly Wnt5a, are involved in the progression of various types of cancers. Here, we show that higher expression of Ror1 and Wnt5b, but not Ror2, are associated with poorer prognosis of PDAC patients, and that Ror1 and Wnt5b are expressed highly in a type of PDAC cell lines, PANC-1 cells. Knockdown of either Ror1 or Wnt5b in PANC-1 cells inhibited their proliferation significantly in vitro, and knockout of Ror1 in PANC-1 cells resulted in a significant inhibition of tumor growth in vivo. Furthermore, we show that Wnt5b-Ror1 signaling in PANC-1 cells promotes their proliferation in a cell-autonomous manner by modulating our experimental setting in vitro. Collectively, these findings indicate that Wnt5b-Ror1 signaling might play an important role in the progression of some if not all of PDAC by promoting proliferation.

  2024年03月, Genes to cells : devoted to molecular & cellular mechanisms, 英語, 国際誌

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• Rho family small GTPase Rif regulates Wnt5a-Ror1-Dvl2 signaling and promotes lung adenocarcinoma progression

  Michiru Nishita, Koki Kamizaki, Kyoka Hoshi, Kana Aruga, Ikumi Nishikaku, Hiroshi Shibuya, Kunio Matsumoto, Yasuhiro Minami

  Elsevier BV, 2023年09月, Journal of Biological Chemistry, 105248 - 105248

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• Expression of Ferredoxin1 in cisplatin‑resistant ovarian cancer cells confers their resistance against ferroptosis induced by cisplatin.

  Ryosuke Takahashi, Koki Kamizaki, Keitaro Yamanaka, Yoshito Terai, Yasuhiro Minami

  Ovarian cancer (OC) is a refractory cancer that shows recurrence due to the acquisition of resistance to anticancer drugs, including cisplatin. However, the molecular mechanism underlying the acquisition of cisplatin resistance by cancer cells remains largely unknown. In the present study, two sets of ovarian endometrioid carcinoma cell lines were used: The parental A2780 cell line, the OVK18 cell line, and their derived cisplatin‑resistant cells. It was found that cisplatin could induce ferroptosis in these parental cells by enhancing mitochondrial membrane potential and lipid peroxidation as assessed by flow cytometric analysis, and that expression of Ferredoxin1 (Fdx1), an iron‑sulfur protein localized to the mitochondria, could be upregulated in cisplatin‑resistant cells in the absence of cisplatin. Intriguingly, it was shown that the siRNA‑mediated depletion of Fdx1 in cisplatin‑resistant cells resulted in enhanced ferroptosis by increasing the mitochondrial membrane potential and lipid peroxidation induced by cisplatin. By examining Fdx1 expression with immunohistochemical analysis in clinical specimens from patients with OC, higher expression of Fdx1 was detected in cisplatin‑resistant specimens than in cisplatin‑sensitive specimens. Collectively, these results indicated that Fdx1 may be a novel and suitable diagnostic/prognostic marker and therapeutic molecular target for the treatment of cisplatin‑resistant OC.

  2023年06月, Oncology reports, 49(6) (6), 英語, 国際誌

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• Molecular mechanisms underlying the promotion of wound repair by coenzyme Q10: PI3K/Akt signal activation via alterations to cell membrane domains.

  Tatsuyuki Kurashiki, Yosuke Horikoshi, Koki Kamizaki, Teppei Sunaguchi, Kazushi Hara, Masaki Morimoto, Yoshinori Kitagawa, Kazuhiro Nakaso, Akihiro Otsuki, Tatsuya Matsura

  Coenzyme Q10 (CoQ10) promotes wound healing in vitro and in vivo. However, the molecular mechanisms underlying the promoting effects of CoQ10 on wound repair remain unknown. In the present study, we investigated the molecular mechanisms through which CoQ10 induces wound repair using a cellular wound-healing model. CoQ10 promoted wound closure in a dose-dependent manner and wound-mediated cell polarization after wounding in HaCaT cells. A comparison with other CoQ homologs, benzoquinone derivatives, and polyisoprenyl compounds suggested that the whole structure of CoQ10 is required for potent wound repair. The phosphorylation of Akt after wounding and the plasma membrane translocation of Akt were elevated in CoQ10-treated cells. The promoting effect of CoQ10 on wound repair was abrogated by co-treatment with a phosphatidylinositol 3-kinase (PI3K) inhibitor. Immuno-histochemical and biochemical analyses showed that CoQ10 increased the localization of caveolin-1 (Cav-1) to the apical membrane domains of the cells and the Cav-1 content in the membrane-rich fractions. Depletion of Cav-1 suppressed CoQ10-mediated wound repair and PI3K/Akt signaling activation in HaCaT cells. These results indicated that CoQ10 increases the translocation of Cav-1 to the plasma membranes, activating the downstream PI3K/Akt signaling pathway, and resulting in wound closure in HaCaT cells.

  2022年05月, Journal of clinical biochemistry and nutrition, 70(3) (3), 222 - 230, 英語, 国内誌

  研究論文（学術雑誌）


• The Ror-Family Receptors in Development, Tissue Regeneration and Age-Related Disease

  Mitsuharu Endo, Koki Kamizaki, Yasuhiro Minami

  The Ror-family proteins, Ror1 and Ror2, act as receptors or co-receptors for Wnt5a and its related Wnt proteins to activate non-canonical Wnt signaling. Ror1 and/or Ror2-mediated signaling plays essential roles in regulating cell polarity, migration, proliferation and differentiation during developmental morphogenesis, tissue-/organo-genesis and regeneration of adult tissues following injury. Ror1 and Ror2 are expressed abundantly in developing tissues in an overlapping, yet distinct manner, and their expression in adult tissues is restricted to specific cell types such as tissue stem/progenitor cells. Expression levels of Ror1 and/or Ror2 in the adult tissues are increased following injury, thereby promoting regeneration or repair of these injured tissues. On the other hand, disruption of Wnt5a-Ror2 signaling is implicated in senescence of tissue stem/progenitor cells that is related to the impaired regeneration capacity of aged tissues. In fact, Ror1 and Ror2 are implicated in age-related diseases, including tissue fibrosis, atherosclerosis (or arteriosclerosis), neurodegenerative diseases, and cancers. In these diseases, enhanced and/or sustained (chronic) expression of Ror1 and/or Ror2 is observed, and they might contribute to the progression of these diseases through Wnt5a-dependent and -independent manners. In this article, we overview recent advances in our understanding of the roles of Ror1 and Ror2-mediated signaling in the development, tissue regeneration and age-related diseases, and discuss their potential to be therapeutic targets for chronic inflammatory diseases and cancers.

  Frontiers Media SA, 2022年04月, Frontiers in Cell and Developmental Biology, 10

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• Autonomous and intercellular chemokine signaling elicited from mesenchymal stem cells regulates migration of undifferentiated gastric cancer cells.

  Daiki Okamoto, Natsuko Yamauchi, Gosuke Takiguchi, Michiru Nishita, Yoshihiro Kakeji, Yasuhiro Minami, Koki Kamizaki

  Accumulating evidence demonstrates that bone marrow (BM)-derived mesenchymal stem cells (MSCs) play critical roles in regulating progression of various types of cancer. We have previously shown that Wnt5a-Ror2 signaling in MSCs induces expression of CXCL16, and that CXCL16 secreted from MSCs then binds to its cognate receptor CXCR6 on the surface of an undifferentiated gastric cancer cell line MKN45 cells, eventually leading to proliferation and migration of MKN45 cells. However, it remains unclear about a possible involvement of another (other) cytokine(s) in regulating progression of gastric cancer. Here, we show that CXCL16-CXCR6 signaling is also activated in MSCs through cell-autonomous machinery, leading to upregulated expression of CCL5. We further show that CCR1 and CCR3, receptors of CCL5, are expressed on the surface of MKN45 cells, and that CCL5 secreted from MSCs promotes migration of MKN45 cells presumably via its binding to CCR1/CCR3. These data indicate that cell-autonomous CXCL16-CXCR6 signaling activated in MSCs upregulates expression of CCL5, and that subsequent activation of CCL5-CCR1/3 signaling in MKN45 cells through intercellular machinery can promote migration of MKN45 cells. Collectively, these findings postulate the presence of orchestrated chemokine signaling emanated from MSCs to regulate progression of undifferentiated gastric cancer cells.

  2022年03月, Genes to cells : devoted to molecular & cellular mechanisms, 27(5) (5), 368 - 375, 英語, 国際誌

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• Characterization of morphological alterations in micropapillary adenocarcinoma of the lung using an established cell line.

  Dai Sonoda, Koki Kamizaki, Yukiko Matsuo, Kana Aruga, Masashi Mikubo, Keishi Yamashita, Michiru Nishita, Yasuhiro Minami, Yukitoshi Satoh

  Micropapillary adenocarcinoma of the lung is a type of cancer associated with a poor prognosis and is characterized by the presence of tumor cells with a ring‑like glandular structure floating within alveolar spaces. In the present study, the association between its morphological, biochemical and immunohistochemical characteristics, and malignancy was investigated using the KU‑Lu‑MPPt3 cell line established from a patient with MIP adenocarcinoma. Two subpopulations of KU‑Lu‑MPPt3 cells, namely adhesive (AD) and clumpy and suspended (CS) cells, were prepared and subjected to DNA microarray, reverse transcription‑quantitative PCR, western blot and immunostaining analyses. Protein expression patterns were compared between the cell types and their derived tissues using immunostaining. The results revealed similar protein expression patterns between the tumor cells found in the alveolar spaces and CS cells, which exhibited morphological characteristic of MIP adenocarcinoma. Based on the results of DNA microarray analysis, the present study then focused on Akt and focal adhesion kinase (FAK), which were markedly activated in the KU‑Lu‑MPPt3 CS and AD cells, respectively. Following KU‑Lu‑MPPt3 CS cell plating onto collagen‑coated culture dishes, some cells exhibited a transformation of their morphology into KU‑Lu‑MPPt3 AD‑like cells within a few days, and their Akt and FAK activities were similar to those of the AD cells. Additionally, the inhibition of Akt and FAK activities with Akt and FAK inhibitors reduced KU‑Lu‑MPPt3 CS cell adhesion and proliferation. Thus, the aforementioned results indicated that the phosphorylation of FAK and Akt may play a crucial role in the regulation of KU‑Lu‑MPPt3 CS cell adhesion and proliferation, respectively. Furthermore, the malignant potential of MIP adenocarcinoma may be attributed to these morphological and biochemical alterations in the KU‑Lu‑MPPt3 cells.

  2022年01月, Oncology reports, 47(1) (1), 英語, 国際誌

  研究論文（学術雑誌）


• Oncogenic E6 and/or E7 proteins drive proliferation and invasion of human papilloma virus‑positive head and neck squamous cell cancer through upregulation of Ror2 expression.

  Mehmet Ozgur Avincsal, Koki Kamizaki, Naoe Jimbo, Hirotaka Shinomiya, Ken-Ichi Nibu, Michiru Nishita, Yasuhiro Minami

  Ror2 (receptor tyrosine kinase like orphan receptor 2) is highly expressed in various types of cancers; in the majority of these cancers, Ror2 expression is associated with more aggressive disease states. Recently, it has been reported that Ror2 is highly expressed in human papilloma virus (HPV)‑positive head and neck squamous cell cancer (HNSCC) cell lines, presumably indicating that Ror2 plays a critical role in HPV‑related cancers. However, the function of Ror2 in HPV‑positive HNSCC is currently unknown. Here, we first examined the expression levels of Ror2 in clinical specimens from patients with HPV‑negative and HPV‑positive oropharyngeal squamous cell cancer (OPSCC) via immunohistochemical analysis. We found that Ror2 was expressed in both HPV‑negative and HPV‑positive OPSCC tissues. We then confirmed that HPV‑positive HNSCC cell line, UPCI:SCC152 cells, express Ror2 higher than HPV‑negative cell lines as previously reported. Suppressed expression of HPV E6/7 resulted in reduced expression levels of Ror2. We also revealed that Ror2 downregulation significantly inhibited the proliferation of UPCI:SCC152 cells without inducing apoptosis. Moreover, Ror2 knockdown decelerated G1/S phase progression and abrogated invasive migration of UPCI:SCC152 cells. These results provide strong evidence that E6 and/or E7 oncoproteins regulate the progression of HPV‑positive HNSCC by upregulating Ror2 expression, suggesting that Ror2 could potentially be a novel target in HPV‑related cancers.

  2021年07月, Oncology reports, 46(1) (1), 英語, 国際誌

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• Role of noncanonical Wnt ligands and Ror‐family receptor tyrosine kinases in the development, regeneration, and diseases of the musculoskeletal system

  Koki Kamizaki, Mitsuharu Endo, Yasuhiro Minami, Yasuhiro Kobayashi

  The Ror-family receptor tyrosine kinases (RTKs), consisting of Ror1 and Ror2, play crucial roles in morphogenesis and formation of various tissues/organs, including the bones and skeletal muscles, the so-called musculoskeletal system, during embryonic development, by acting as receptors or coreceptors for a noncanonical Wnt protein Wnt5a. Furthermore, several lines of evidence have indicated that Ror1 and/or Ror2 play critical roles in the regeneration and maintenance of the musculoskeletal system in adults. Considering the anatomical and functional relationship between the skeleton and skeletal muscles, their structural and functional association might be tightly regulated during their embryonic development, development after birth, and their regeneration after injury in adults. Importantly, in addition to their congenital anomalies, much attention has been paid onto the age-related disorders of the musculoskeletal system, including osteopenia and sarcopenia, which affect severely the quality of life. In this article, we overview recent advances in our understanding of the roles of Ror1- and/or Ror2-mediated signaling in the embryonic development, regeneration in adults, and congenital and age-related disorders of the musculoskeletal system and discuss possible therapeutic approaches to locomotive syndromes by modulating Ror1- and/or Ror2-mediated signaling.

  Wiley, 2020年01月, Developmental Dynamics, 250(1) (1), 27 - 38, 英語, 国際誌

  研究論文（学術雑誌）


• α-Tocopherol promotes HaCaT keratinocyte wound repair through the regulation of polarity proteins leading to the polarized cell migration

  Yosuke Horikoshi, Kouki Kamizaki, Takehiko Hanaki, Masaki Morimoto, Yoshinori Kitagawa, Kazuhiro Nakaso, Chiaki Kusumoto, Tatsuya Matsura

  In many developed countries including Japan, how to care the bedridden elderly people with chronic wounds such as decubitus becomes one of the most concerned issues. Although antioxidant micronutrients including vitamin E, especially α-tocopherol (α-Toc), are reported to shorten a period of wound closure, the promoting effect of α-Toc on wound healing independent of its antioxidant activity remains to be fully elucidated. The aim of this study was to examine whether α-Toc affects wound-mediated HaCaT keratinocyte polarization process including the recruitment of polarity regulating proteins, leading to wound repair independently of its antioxidant activity. We investigated the effects of α-Toc and other antioxidants such as Trolox, a cell-permeable α-Toc analog on the migration, proliferation, and cell polarization of HaCaT keratinocytes after wounding. We analyzed the localization and complex formation of polarity proteins, partitioning defective 3 (Par3), and atypical protein kinase C (aPKC), and aPKC activity by immunohistochemistry, immunoprecipitation analyses, and in vitro kinase assays, respectively. α-Toc but not other antioxidants enhanced the wound closure and cell polarization in HaCaT keratinocytes after wounding. α-Toc regulated the localization and complex formation of Par3 and aPKC during wound healing. Knockdown of aPKC or Par3 abrogated α-Toc-mediated promotion of the wound closure and cell polarization in HaCaT keratinocytes. Furthermore, aPKC kinase activity was significantly increased in α-Toc-treated cells through activation of phosphatidylinositol 3-kinase/Akt signaling pathway. These results suggest that α-Toc promotes HaCaT keratinocyte wound repair by regulating the aPKC kinase activity and the formation of aPKC-Par3 complex. © 2017 BioFactors, 44(2):180-191, 2018.

  Wiley, 2018年03月, BioFactors, 44(2) (2), 180 - 191, 英語, 国際誌

  研究論文（学術雑誌）


• Ror2 signaling regulates Golgi structure and transport through IFT20 for tumor invasiveness

  Michiru Nishita, Seung-Yeol Park, Tadashi Nishio, Koki Kamizaki, ZhiChao Wang, Kota Tamada, Toru Takumi, Ryuju Hashimoto, Hiroki Otani, Gregory J. Pazour, Victor W. Hsu, Yasuhiro Minami

  Signaling through the Ror2 receptor tyrosine kinase promotes invadopodia formation for tumor invasion. Here, we identify intraflagellar transport 20 (IFT20) as a new target of this signaling in tumors that lack primary cilia, and find that IFT20 mediates the ability of Ror2 signaling to induce the invasiveness of these tumors. We also find that IFT20 regulates the nucleation of Golgi-derived microtubules by affecting the GM130-AKAP450 complex, which promotes Golgi ribbon formation in achieving polarized secretion for cell migration and invasion. Furthermore, IFT20 promotes the efficiency of transport through the Golgi complex. These findings shed new insights into how Ror2 signaling promotes tumor invasiveness, and also advance the understanding of how Golgi structure and transport can be regulated.

  Springer Science and Business Media LLC, 2017年12月, Scientific Reports, 7(1) (1), 1 - 1, 英語, 国際誌

  研究論文（学術雑誌）


• The Ror1 receptor tyrosine kinase plays a critical role in regulating satellite cell proliferation during regeneration of injured muscle

  Koki Kamizaki, Ryosuke Doi, Makoto Hayashi, Takeshi Saji, Motoi Kanagawa, Tatsushi Toda, So-ichiro Fukada, Hsin-Yi Henry Ho, Michael Eldon Greenberg, Mitsuharu Endo, Yasuhiro Minami

  The Ror family receptor tyrosine kinases, Ror1 and Ror2, play important roles in regulating developmental morphogenesis and tissue- and organogenesis, but their roles in tissue regeneration in adult animals remain largely unknown. In this study, we examined the expression and function of Ror1 and Ror2 during skeletal muscle regeneration. Using an in vivo skeletal muscle injury model, we show that expression of Ror1 and Ror2 in skeletal muscles is induced transiently by the inflammatory cytokines, TNF-α and IL-1β, after injury and that inhibition of TNF-α and IL-1β by neutralizing antibodies suppresses expression of Ror1 and Ror2 in injured muscles. Importantly, expression of Ror1, but not Ror2, was induced primarily in Pax7-positive satellite cells (SCs) after muscle injury, and administration of neutralizing antibodies decreased the proportion of Pax7-positive proliferative SCs after muscle injury. We also found that stimulation of a mouse myogenic cell line, C2C12 cells, with TNF-α or IL-1β induced expression of Ror1 via NF-κB activation and that suppressed expression of Ror1 inhibited their proliferative responses in SCs. Intriguingly, SC-specific depletion of Ror1 decreased the number of Pax7-positive SCs after muscle injury. Collectively, these findings indicate for the first time that Ror1 has a critical role in regulating SC proliferation during skeletal muscle regeneration. We conclude that Ror1 might be a suitable target in the development of diagnostic and therapeutic approaches to manage muscular disorders.

  American Society for Biochemistry & Molecular Biology (ASBMB), 2017年09月, Journal of Biological Chemistry, 292(38) (38), 15939 - 15951, 英語, 国際誌

  研究論文（学術雑誌）


• The estrogen receptor β-PI3K/Akt pathway mediates the cytoprotective effects of tocotrienol in a cellular Parkinson's disease model

  Kazuhiro Nakaso, Naoko Tajima, Yosuke Horikoshi, Masato Nakasone, Takehiko Hanaki, Kouki Kamizaki, Tatsuya Matsura

  Tocotrienols (T3s) are members of the vitamin E family, have antioxidant properties, and are promising candidates for neuroprotection in the pathogenesis of neurodegenerative disorders such as Parkinson's disease (PD). However, whether their antioxidant capacities are required for their cytoprotective activity remains unclear. In this regard, the antioxidant-independent cytoprotective activity of T3s has received considerable attention. Here, we investigated the signaling pathways that are induced during T3-dependent cytoprotection of human neuroblastoma SH-SY5Y cells, as these cells are used to model certain elements of PD. T3s were cytoprotective against 1-methyl-4-phenylpyridinium ion (MPP(+)) and other PD-related toxicities. γT3 and δT3 treatments led to marked activation of the PI3K/Akt signaling pathway. Furthermore, we identified estrogen receptor (ER) β as an upstream mediator of PI3K/Akt signaling following γT3/δT3 stimulation. Highly purified γT3/δT3 bound to ERβ directly in vitro, and knockdown of ERβ in SH-SY5Y cells abrogated both γT3/δT3-dependent cytoprotection and Akt phosphorylation. Since membrane-bound ERβ was important for the signal-related cytoprotective effects of γT3/δT3, we investigated receptor-mediated caveola formation as a candidate for the early events of signal transduction. Knockdown of caveolin-1 and/or caveolin-2 prevented the cytoprotective effects of γT3/δT3, but did not affect Akt phosphorylation. This finding suggests that T3s and, in particular, γT3/δT3, exhibit not only antioxidant effects but also a receptor signal-mediated protective action following ERβ/PI3K/Akt signaling. Furthermore, receptor-mediated caveola formation is an important event during the early steps following T3 treatment.

  Elsevier BV, 2014年09月, Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1842(9) (9), 1303 - 1312, 英語, 国際誌

  研究論文（学術雑誌）

• Wnt-Ror2シグナルによる 間葉系前駆細胞の機能制御

  第9回日本筋学会学術集会, 2023年08月


• Wnt-Ror2 signaling in mesenchymal progenitor cells contributes to maintenance and adipogenic degeneration of the skeletal muscle

  Wnt2022, 2022年11月


• Rif regulates Wnt5a-Ror1 signaling to induce filopodia-mediated progression of lung adenocarcinoma cells.

  第81回日本癌学会学術総会, 2022年09月


• Ror2による骨格筋間葉系前駆細胞の機能制御機構

  第８回日本筋学会学術集会, 2022年08月


• Wnt5a-Rorシグナルが制御する細胞膜突起形成とがん細胞浸潤

  第94回日本生化学大会, 2021年11月


• Ror1-Rifシグナルは糸状突起形成を介して肺腺がん細胞の浸潤と血管擬態を促進する

  第80回日本癌学会学術総会, 2021年10月


• Wnt5a-Ror1 signaling promotes invasion of lung adenocarcinoma cells through Rif-mediated formation of filopodia

  若手支援技術講習会

  口頭発表（一般）


• 骨格筋の異所性脂肪蓄積におけるRor2の機能解析

  第7回神緑会YIA

  ポスター発表


• 骨格筋組織幹細胞におけるRor1およびRor2の機能解析

  第5回筋学会学術集会

  口頭発表（一般）


• Role of Ror family tyrosine kinases in skeletal muscle

  9th FAOPS

  ポスター発表


• Ror2 regulates adipogenic differentiation of mesenchymal progenitor cells in the skeletal muscle

  ASCB EMBO meeting 2018

  ポスター発表


• Ror2は骨格筋における間葉系前駆細胞の脂肪分化に重要である

  第6回若手による骨格筋細胞研究会

  ポスター発表


• 骨格筋再生過程におけるRorファミリー受容体型チロシンキナーゼの機能解析

  第10回シグナルネットワーク研究会

  口頭発表（一般）


• 受容体型チロシンキナーゼRor1は衛星細胞の増殖を制御することで骨格筋再生に寄与する

  第５回若手による骨格筋細胞研究会

  口頭発表（一般）


• 骨格筋修復過程におけるRor1を介した衛星細胞の増殖制御

  第4回神緑会ヤングインベスティゲーターアワード(YIA)発表会

  ポスター発表


• 受容体型チロシンキナーゼRor1は骨格筋損傷後の衛星細胞の増殖に重要である

  第2回日本筋学会学術集会

  ポスター発表


• Crucial role of the Ror-family receptor tyrosine kinases in regulating tissue stem cells

  University of Washington and Kobe University Kick-off Symposium

  ポスター発表


• TNFaによって誘導されたRor1は筋芽細胞の増殖を促進する

  第38回日本分子生物学会年会 第88回日本生化学会大会 合同大会

  ポスター発表


• Wnt5a-Ror2 signaling induces expression of the ciliary protein IFT20 to regulate the intensity of the Golgi apparatus and reorientation of the centrosome during tumor cell invasion

  Epithelial tubulology The second international meeting

  ポスター発表


• 筋芽細胞におけるRor1のNF-kBを介した発現誘導機構

  第7回シグナルネットワーク研究会

  口頭発表（一般）


• Role of NF-kB-mediated expression of Ror1 during skeletal muscle regeneration

  University of Washington and Kobe University International Joint Symposium

  ポスター発表


• CoQ10によるプロテインキナーゼCの機能制御を介した創傷治癒促進効果

  コエンザイムQ10研究会, 2014年01月

  口頭発表（一般）

• Rifによる膵がん細胞のFerroptosis抵抗メカニズムの解明

  紙崎 孝基

  日本学術振興会, 科学研究費助成事業, 若手研究, 神戸大学, 2024年04月01日 - 2027年03月31日


• Ror1-Rifシグナルによる血管擬態メカニズムの解明

  紙崎 孝基

  日本学術振興会, 科学研究費助成事業, 若手研究, 神戸大学, 2021年04月01日 - 2024年03月31日

  申請者らはこれまでに、肺腺がん細胞においてRorファミリー受容体であるRor1が低分子量Gタンパク質であるRifと結合すること、Ror1およびRifは糸状突起の形成に重要であることを見出してきた。また、Ror1およびRifの発現量は肺腺がん患者の予後と相関することから、Ror1およびRifによって形成される糸状突起は肺腺がんの進展に重要であることが想定されるが、Ror1およびRifが糸状突起を形成する分子機構や、糸状突起がどのようにして肺腺がんの進展に寄与するかは十分に解明されていない。 本年度の解析から、RifはRor1の細胞内局在を制御することでWnt5a-Ror1シグナルを制御していることが明らかとなった。さらに、RifおよびRor1によって形成される糸状突起は肺腺がん細胞の増殖および浸潤において重要な役割を担っていること、特に浸潤過程においては肺腺がん細胞の極性化やMMP9の分泌に寄与していることを見出した。また、糸状突起は肺腺がん細胞同士の細胞間相互作用を介して血管擬態の形成にも寄与することを見出した。また興味深いことに、Ror1およびRifの発現を抑制すると血管擬態の形成が抑制されるとともに、ミトコンドリア形態にも異常が生じることが明らかとなった。ミトコンドリアと血管擬態の関係性については不明であるため、次年度はRifおよびRor1によって形成される糸状突起とミトコンドリア形態制御、血管擬態形成の関係性について解析を進めていく予定である。


• Ror受容体を介した新たな骨格筋再生・変性制御メカニズムの解明

  紙崎 孝基

  日本学術振興会, 科学研究費助成事業, 特別研究員奨励費, 神戸大学, 2019年04月 - 2020年03月

  骨格筋に常在する間葉系前駆細胞(Mesenchymal Progenitor cells: MPCs)は、骨格筋の病的状態下において脂肪細胞に分化し、骨格筋における異所性脂肪組織の蓄積を誘導し筋機能の低下を引き起こす。このことから、MPCsによる異所性脂肪組織の蓄積メカニズムの解明は喫緊の課題とされている。 我々はこれまでにMPCsにおいて受容体型チロシンキナーゼRor2が高発現していることを見出していたが(未発表)、その機能については不明であった。そこで、本研究ではMPCsにおけるRor2の機能解明を目的とした解析を行った。まず、MPCs特異的にRor2を欠失させることのできるRor2コンディショナルノックアウトマウスを作製し、当該マウスを用いた解析を行った。コントロールマウスとRor2 cKOマウスの前脛骨筋にグリセロールを投与し、異所性脂肪組織の蓄積を伴う骨格筋損傷を誘導したところ、Ror2 cKOマウスでは異所性脂肪組織の蓄積が抑制された。また、このときRor2のリガンドとして知られるWnt5aおよびその近縁分子であるWnt5bの発現変動について解析したところ、Wnt5bのみグリセロール投与後に発現上昇することが確認された。さらに、野生型マウスから単離・培養したMPCsを用いた解析から、Wnt5b-Ror2シグナルはMPCsの増殖を促進することが明らかとなった。実際、骨格筋の変性が生じる際にはMPCsの数が異常に増加することが知られているが、そのメカニズムについては不明な点が多い。以上のことから、骨格筋の病的状態下では、Wnt5b-Ror2シグナルによってMPCsの増殖が過剰に促進されることで、異所性脂肪組織の蓄積が生じる可能性が示唆された。

• 骨格筋内脂肪組織（ＩＭＡＴ；Ｉｎｔｒａｍｕｓｃｕｌａｒ ａｄｉｐｏｓｅ ｔｉｓｓｕｅ）形成抑制物質をスクリーニングする方法、及びＩＭＡＴ形成抑制用組成物

  特願2023-104009

  特許権


• プラチナ製剤耐性卵巣がんの検出方法、及び腫瘍の治療又は予防候補物質をスクリーニングする方法

  特願2023-104011

  特許権